Topical delivery of a pharmaceutical agent depends on the ability of the agent to be released from its formulation and subsequently permeate a barrier, such as skin, nails, and/or hooves, to get to an area in need of such treatment. Non-invasive methods that require minimal management by a patient are preferred.
Certain methods, such as iontophoresis, rely on creating an electrical potential gradient over the barrier to enhance permeation of the pharmaceutical agent. These methods are primarily directed to drugs having a net charge.
For most drugs, including those that are uncharged or zwitterionic, methods that focus on a chemical potential of a drug in a carrier are useful. The flux of a drug into the body can be enhanced by increasing the chemical potential of the drug in its carrier. This is normally performed by chemical optimization of the drug composition by adjusting the degree of saturation of the drug in the carrier. Advantages to this approach are that the properties of the barrier itself are comparatively less affected and the lag time of initiation for the pharmacological effect is reduced. Two aspects to this approach include: i) creation of an initial high chemical potential of the drug in the composition, and ii) maintenance of a high chemical potential of the drug in the vicinity of the barrier after the application of the composition. It is usually desirable to prepare pharmaceutical compositions which are saturated with respect of the drug. During application, another aspect of the composition is that the solubility and diffusion properties of the drug in the used vehicle must preclude depletion of the drug in the vicinity of the barrier. Examples of compositions used for this purpose are microemulsions and emulsions.
Another approach towards keeping the composition saturated is the use of an excess amount of drug (non-solubilised) in the carrier, whereby the drug is subsequently dissolved as it replaces the drug which has penetrated through the barrier.
Yet another approach is the use of a supersaturated composition of the drug. Here, the driving force of the drug to penetrate the barrier is higher than in the saturated composition, since the drug in a supersaturated composition has higher chemical potential in comparison with the corresponding saturated composition. For example, such compositions have been prepared according to the following means or principles: i) dissolving the drug at temperatures and/or pressures at which the solubility of the drug is higher as compared to those temperatures and/or pressures that are relevant for medication (W. L. Chou and S. Riegelmann, J. Pharm. Sci., Vol. 60, No. 9, pp. 1281-1302, 1971; WO 97/10812), ii) mixing a saturated drug solution with a non-solvent therefor, thereby performing a merely physical operation, in situ or prior to application, with or without the presence of an antinucleating agent (U.S. Pat. No. 4,940,701, U.S. Pat. No. 4,767,751), iii) solvent evaporation to the surrounding air (Coldman et al., J. Pharm. Sci., 58, No. 9 (1969), pp. 1098-1102), iv) solvent penetration into the human body, v) water uptake into the composition from the human body, or vi) pH-changes in the composition caused by H+ uptake from the human body.
U.S. Pat. No. 6,083,518 discloses a biologically active composition comprising a solution of an active agent dissolved in a glass-forming carrier, which carrier comprises a glass-forming substance containing a plasticizer.
U.S. Pat. No. 6,537,576 relates to a novel biologically active composition which comprises a biologically active agent to be released therefrom, said biologically active agent being dissolved and/or dispersed in a supersaturated state within a carrier, which carrier comprises a liquid and/or solid non-crystalline ester and/or polyester matrix, and where the precipitation of said biologically active agent is substantially, or completely, inhibited therein.
From cosmetic perspective the amount of formulation (e.g., ointment, cream, gel, lotion, stick etc.) that may be applied on a body surface is limited to the range of about 1-10 mg/cm2, thus producing a thin film with a surface to volume ratio favoring evaporation of volatile parts. The formulation therefore inevitably undergoes rapid changes in composition. The limited amount of formulation that may be applied further emphasizes drug accessibility as an important factor for penetration.
Certain drug carriers are prone to phase separation based on the content of solvents and polymers in the carriers. It is desirable to have topical compositions of a single phase to ensure uniform application and efficient use of the active drug.
There is an ongoing need to provide stable topical compositions that permit increased bioavailability of pharmaceutical agents to areas in need.